Disability threatens the independence of many older adults and results in substantial late-life health care needs and associated expenditures. Sarcopenia, defined as loss of muscle mass and strength, plays a central role in disability. Our long-term goals are to gain insight into the processes that underlie the development of sarcopenia and disability and to identify possible strategies that reduce the risk of sarcopenia and disability. In the first cycle of this R01, we examined the hypothesis that oxidative stress contributes to loss of muscle strength, decline in physical performance, disability, and mortality in older adults, and our findings support this paradigm. We now build upon the previous findings with important new preliminary data that implicate advanced glycation end products (AGEs) with poor muscle strength and mortality. AGEs are bioactive molecules that have recently been identified in the pathogenesis of multiple chronic diseases. AGEs occur in foods that have been cooked at very high temperatures, and ingested AGEs upregulate oxidative stress and inflammation through receptor for AGE (RAGE). RAGE also circulates in the blood and may serve as a decoy to bind free AGEs and prevent AGE-RAGE binding and activation of inflammation. Based upon knowledge of the AGE-RAGE pathway and our preliminary data, we hypothesize that older adults with elevated AGEs and circulating RAGE have an increased risk of sarcopenia, impaired physical performance, disability, and mortality. We propose to characterize the relationship between AGEs and circulating RAGE with these outcomes in adults from two different NIH-supported prospective, population-based cohort studies of aging, the Women's Health and Aging Study in Baltimore, and the InCHIANTI study in Italy. Our proposed studies will expand the knowledge of AGEs and their circulating receptors into a novel area of investigation that focuses on sarcopenia and aging in community-dwelling adults. If elevated serum AGEs are predictive of poor muscle strength, disability, and mortality, it would identify AGEs as a possible target for the prevention of disability in older adults. AGEs are a potentially modifiable risk factor, as circulating AGEs can be lowered by dietary modification and by pharmacological intervention. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between advanced glycation end products, bioactive compounds found in high amounts in the western diet, and muscle weakness, disability, and mortality in older adults.